ABSTRACT
Most tissues are continuously renovated through the division of stem cells and the death of old or damaged cells, which is known as cell turnover rate (CTOR). Despite being in steady state, tissues have different population dynamics and leading to diverse clonality levels. Here, we propose and test that cell population dynamics can be a cancer driver. We employed the evolutionary software esiCancer to show that CTOR, within a range comparable to what is observed in human tissues, can amplify the risk of a mutation due to ancestral selection (ANSEL). In a high CTOR tissue, a mutated ancestral cell is likely to be selected and persist over generations, which leads to a scenario of elevated ANSEL profile, characterized by few niches of large clones, which does not occur in low CTOR. We found that CTOR is significantly associated with the risk of developing cancer, even when correcting for mutation load, indicating that population dynamics per se is a cancer driver. This concept is central to understanding cancer risk and for the design of new therapeutic interventions that minimize the contribution of ANSEL in cancer growth.
ABSTRACT
The evolution of cancer is inferred mainly from samples taken at discrete points that represent glimpses of the complete process. In this study, we present esiCancer as a cancer-evolution simulator. It uses a branching process, randomly applying events to a diploid oncogenome, altering probabilities of proliferation and death of the affected cells. Multiple events that occur over hundreds of generations may lead to a gradual change in cell fitness and the establishment of a fast-growing population. esiCancer provides a platform to study the impact of several factors on tumor evolution, including dominance, fitness, event rate, and interactions among genes as well as factors affecting the tumor microenvironment. The output of esiCancer can be used to reconstruct clonal composition and Kaplan-Meier-like survival curves of multiple evolutionary stories. esiCancer is an open-source, standalone software to model evolutionary aspects of cancer biology. SIGNIFICANCE: This study provides a customizable and hands-on simulation tool to model the effect of diverse types of genomic alterations on the fate of tumor cells.
